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PubMed2001

Epidemiological study of urinary 6beta-hydroxycortisol to cortisol ratios and breast cancer risk.

The ratio of urinary 6beta-hydroxycortisol:cortisol is a measure of the activity of cytochrome p450 3A4 (CYP3A4). CYP3A4 catalyzes the formation of the genotoxic estrogen, 16alpha-hydroxyestrone. It is also involved in the activation of many other mammary carcinogens, such as the polycyclic aromatic hydrocarbons and heterocyclic amines. We evaluated the association between urinary cortisol ratios and breast cancer risk in a subgroup of women who participated in a population-based case-control study in Shanghai. Overnight urine samples from 246 case-control pairs were assayed for 6beta-hydroxycortisol (6beta-OHC) to cortisol. The urine samples from all of the breast cancer patients were collected before any chemotherapy or radiotherapy. In-person interviews were conducted to obtain comprehensive information on dietary habits, reproductive history, and other lifestyle factors. The median levels of 6beta-OHC:cortisol ratios were 2.61 in cases and 2.16 in controls, a 20.8% difference (P < 0.001). The case-control difference was larger in women over 45 years of age (31.3% difference; P < 0.001) than younger women (6.0%; P = 0.45). After adjusting for confounding variables, the risks of breast cancer were increased from 1.0 (reference) to 1.6 [95% confidence interval (CI), 0.9-3.1], 2.2 (95% CI, 1.1-4.2), and 3.7 (95% CI, 1.9-7.4; P for trend, <0.001) with increasing levels of 6beta-OHC:cortisol ratios. The positive association was more pronounced among older women (>45 years) than among younger women (< or = 45 years). The adjusted odds ratios associated with the highest cortisol ratio were 6.0 (95%CI, 2.2-16.1) among older women and 2.2 (95%CI, 0.8-6.1) among younger women. The association of the 6beta-OHC:cortisol ratio was stronger among older women who had a high body mass index, late age at menopause, and early age at menarche (factors related to high endogenous estrogen exposure) than those who did not have these factors. These findings are consistent with the role of CYP3A4 in estrogen and carcinogen metabolism and suggest that high CYP3A4 activity may be a risk factor for breast cancer risk.

Adult↗
PubMed2001

Preferential growth stimulation of mammary glands over uterine endometrium in female rats by a naturally occurring estradiol-17beta-fatty acid ester.

We hypothesize that the endogenously present lipoidal estrogen fatty acid esters may have a stronger mitogenic action in the fat-rich mammary tissues than in the uterus. To test this hypothesis, we compared the activity of estradiol-17beta-stearate (E(2)-17beta-S) with that of estradiol-17beta (E(2)) in stimulating the growth of mammary glandular cells versus the growth of uterine endometrial cells in ovariectomized female Sprague Dawley rats. Experimentally, an estimated 0.5 or 5 nmol of E(2)-17beta-S or E(2) was released daily to ovariectomized female rats through an Alzet pump implanted under the back skin of the animal for 10 or 23 days. The growth-stimulatory effect of E(2)-17beta-S and E(2) on mammary glandular cells was determined according to 5-bromo-2'-deoxyuridine labeling indices, and their effect on the uterus was determined by measuring both the 5-bromo-2'-deoxyuridine labeling index and the uterine wet weight. Our results showed that chronic treatment of ovariectomized female rats with 0.5 or 5 nmol/day E(2)-17beta-S for 10 or 23 days had a stronger stimulatory effect on mammary glandular cell proliferation than treatment with equimolar doses of E(2). In the uterus, however, E(2) was more active in stimulating the proliferation of uterine endometrial cells than E(2)-17beta-S at equimolar doses. Our results demonstrated, for the first time, that a naturally occurring estradiol-17beta-fatty acid ester has a differential, strong mitogenic effect in the fat-rich mammary tissues, and this effect was not observed with E(2). It is tempting to suggest that the fatty acid esters of the endogenous estrogens and their bioactive metabolites (e.g., 4-hydroxyestradiol and 16alpha-hydroxyestrone) may be of unique importance for stimulating cell growth and possibly also for inducing tumor formation in the fat-rich mammary tissues as compared with the uterus. More studies are warranted to test these ideas.

Animals↗
PubMed1975

[The thioacetamide-poisoned rat as an animal experimental model for endocrinological studies of estrogen metabolism in chronic liver injury)].

Liver microsomes of rats poisoned with thioacetamide show a significant reduction of cytochrome P-450. Consequently, oxidative reactions of drug metabolism and the estrogen 2-hydroxylase are diminished. Enhancement of microsomal transformation of estradiol to estrone and 16alpha-hydroxyestrone is observed after treatment of rats with thioacetamide, due to diminished metabolism of estradiol by the alternative oxidation at C-2. Estriol formation is reduced by thioacetamide pretreatment. These changes in estrogen breakdown closely correlate with those observed in humans suffering from cirrhosis of the liver. It is concluded that the thioacetamide poisoned rat should be an experimental model suitable for studying estrogen metabolism in liver injury.

Acetamides↗
PubMed2003

Human cytochrome P450 3A7 has a distinct high catalytic activity for the 16alpha-hydroxylation of estrone but not 17beta-estradiol.

Like catechol estrogens, 16alpha-hydroxylated estrogens are hormonally active, chemically reactive, and potentially mutagenic. We report here our novel findings that human CYP3A7 has a distinct high catalytic activity for the NADPH-dependent 16alpha-hydroxylation of estrone (E(1); at 10 nM to 200 microM substrate concentrations) but not for the 16alpha-hydroxylation of 17beta-estradiol (E(2)). At a physiologically relevant low substrate concentration (10 nM), CYP3A7 had a strong catalytic activity for the 16alpha-hydroxylation of E(1), and the ratio of its 16alpha-hydroxylation to 2-hydroxylation was 107%. In addition to 16alpha-hydroxylation, CYP3A7 also had catalytic activity for the 2-, 4-, 6beta-, and 16beta-hydroxylation of E(1). However, when E(2) was the substrate, CYP3A7 had only very weak catalytic activity for its 16alpha-hydroxylation (<6% of E(1) 16alpha-hydroxylation), and the ratio of its 16alpha-hydroxylation to 2-hydroxylation was 10-33%. Enzyme kinetic analysis showed that the maximal velocity and substrate-binding affinity (1/K(m)) for CYP3A7-mediated 16alpha-hydroxylation of E(1) were both approximately 10 times higher than those for E(2), thereby giving the maximal velocity:K(m) ratio of >100 times higher for the 16alpha-hydroxylation of E(1) than for E(2). Given the recent findings that human CYP3A7 is a polymorphic isoform also expressed in adult liver and certain extrahepatic tissues (in addition to fetal tissues), our data raise the possibility that CYP3A7 may be an important catalyst for the local and/or systemic formation of the procarcinogenic 16alpha-hydroxyestrone in women.

Aryl Hydrocarbon Hydroxylases↗
PubMedDate not supplied

New roles for estrogens in rheumatoid arthritis.

Sex hormones appear to play an important role as modulators of autoimmune disease onset/perpetuation. Steroid hormones are implicated in the immune response, with estrogens as enhancers at least of humoral immunity, and androgens and progesterone (and glucocorticoids) as natural immune suppressors. Serum levels of estrogens have been found to be normal in rheumatoid arthritis (RA) patients. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female RA patients as compared to controls, which is most probably due to an increase in local aromatase activity. Thus, available steroid pre-hormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e. TNF alpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular 16 alpha-hydroxyestrone, showing a mitogenic stimulating role. Indeed, recent studies by us indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase in markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on the immune/inflammatory response is exerted by activating the NFkB complex. In conclusion, locally increased estrogens may exert activating effects on synovial cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in RA.

Adult↗
PubMed2005

Estradiol metabolites are potent mitogenic substances for human ovarian cancer cells.

PURPOSE OF INVESTIGATION: The etiology of ovarian cancer appears to be associated with a long-term influence of estrogens. However, evidence is accumulating that certain estradiol metabolites may play a decisive role in the carcinogenesis of estrogen-dependent diseases. In the present study we examined the effect of estradiol metabolites on the proliferation and apoptosis of human ovarian cancer cells in comparison to the effect of their parent substance. METHODS: The ovarian cancer cell line OVCAR-3 was used for the experiments. 17Beta-estradiol (E2), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2) and 16alpha-hydroxyestrone (16-OHE1) were incubated for seven days in the concentration range of 0.01 nM to 10 nM. Proliferation and apoptosis were measured by commercially available assay kits. RESULTS: E2 enhanced proliferation rate and concomitantly reduced apoptotic rate of the ovarian cancer cells at physiological concentrations. 2-OHE2 had no significant effect, whereas 4-OHE2 elicited similar effects on proliferation and apoptotic rate as E2. The greatest proliferative and antiapoptotic effect was observed for 16-OHE1, the values being significantly different to the effects of E2. CONCLUSION: The pattern of endogenous estradiol metabolism may play a role in defining ovarian cancer risk. This may be of importance in certain predisposed women who are treated with hormone therapy in postmenopause.

Apoptosis↗
PubMed2005

Mitogenic estrogen metabolites alter the expression of 17beta-estradiol-regulated proteins including heat shock proteins in human MCF-7 breast cancer cells.

Estrogen metabolites are carcinogenic. The comparative mitogenic activities of 17b-estradiol (E2) and four metabolites, 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 16a-hydroxyestrone (16a-OHE1) and 2-methoxyestradiol (2-ME), were determined in estrogen receptor(ER)-positive MCF-7 human breast cancer cells. Each of the E2 metabolites caused proliferation of the MCF-7 cells, but only E2 and 16a-OHE1 induced a greater than 20-fold increases in transcripts of the progesterone receptor (PR) gene, a classical ER-mediated gene. This suggests that the mitogenic action of E2 and 16a-OHE1 could result from their effects on gene expression via the ER. E2 metabolites altered the expression of E2-regulated proteins including heat shock proteins (Hsps). 16a-OHE1 and 2-ME as well as E2 increased levels of Hsp56, Hsp60, Hsp90a and Hsp110 transcripts, and the patterns of these inductions resembled that of PR. Hsp56 and Hsp60 protein levels were increased by all the E2 metabolites. Levels of the transcripts of 3 E2-upregulated proteins (XTP3-transactivated protein A, protein disulfide isomerase-associated 4 protein and stathmin 1) and an E2-downregulated protein (aminoacylase 1) were also affected by the E2 metabolites. These results suggest that the altered expression of Hsps (especially Hsp56 and Hsp60) by E2 metabolites such as E2, 16a-OHE1 and 2-ME could be closely linked to their mitogenic action.

Amidohydrolases↗
PubMedDate not supplied

Free estrogens and progestogens in benign prostatic hypertrophy.

Studies on the presence of free estrogens and progestogens in human prostates clearly differentiate the benign hypertrophied prostates from normals. Both contained 17 alpha-hydroxypregnenolone 5 beta-pregnane-3, 20-dione, 5 alpha-pregnane-3, 20-dione and 16 alpha-hydroxyestrone. However, presence of 11 alpha-hydroxyprogesterone 20 beta-hydroxypregnenolone, pregnenolone, 17 alpha-hydroxyprogesterone, as well as estrone and estriol exclusively in BPH samples pointed to their possible involvement in the development of benign prostatic hypertrophy.

Aged↗
PubMed1989

The oxidative metabolism of estradiol: inhibition by cimetidine.

Cimetidine, a histamine H2 antagonist, is known to interfere with the metabolism of exogenous drugs by binding to cytochrome P450. We examined the possibility that cimetidine might also inhibit the cytochrome P450-dependent biotransformation of endogenous compounds such as steroid hormones. Utilizing a radiometric assay and normal male volunteers, the acute effect of intravenous cimetidine (300 mg loading dose followed by 50 mg/hr) was determined. The extent of 2-hydroxylation of estradiol was reduced by 25% from 29.6 +/- 4.4% (mean +/- SEM) before, to 22.9 +/- 4.0% during cimetidine infusion (n = 8; p less than 0.0005). Following oral cimetidine (800 mg b.i.d.) for 2 wk, estradiol 2-hydroxylation was decreased by 40% from 31.7 +/- 2.3% to 19.7 +/- 2.4% (n = 9; p less than 0.0001) but 16 alpha-hydroxylation of estradiol was unaffected. Concomitantly, the urinary excretion of 2-hydroxyestrone was decreased by 25% (p less than 0.002) and the serum estradiol concentration was increased by 20% (p less than 0.04). In contrast, ranitidine, a second generation H2 receptor antagonist, had no effect on estradiol hydroxylation following 150 mg b.i.d. for 2 wk. The inhibition of estradiol 2-hydroxylation and the increase in serum estradiol concentrations caused by cimetidine administration may help to account for the symptoms of hyperestrogenization reported in long-term cimetidine therapy.

Administration, Oral↗
PubMed1986

[Dynamics of steroid levels in normal pregnant and parturient woman].

An extract of a relatively small volume of plasma sample was subjected to high performance liquid chromatography (HPLC) to separate unconjugated steroids, which were subsequently assayed by specific radioimmunoassay (RIA) methods. An aliquot of the sample was hydrolysed and the conjugated steroids were also determined in a similar way. These procedures were proved to be accurate, sensitive and specific to each steroid assayed, and were applied to measure steroids in the peripheral blood of pregnant and parturient women, and in the umbilical cord blood at delivery. Steroids assayed were as follows: Estrone (E1), estradiol (E2), estriol (E3), dehydroepiandrosterone (DHA), androstenedione (A), testosterone (T), 16 alpha-hydroxydehydroepiandrosterone (16 alpha-OH-DHA), 16 alpha-hydroxyandrostenedione (16 alpha-OH-A), 16 alpha-hydroxyestrone (16 alpha-OH-E1), DHA-sulfate (DHA-S), and 16 alpha-OH-DHA-sulfate (16 alpha-OH-DHA-S). Two trends were observed in blood concentrations of unconjugated steroids during the course of pregnancy. One group of steroids, E1, E2, E3 and 16 alpha-OH-E1, continued to increase toward the onset of labor. Another group of steroid, A, T, DHA, 16 alpha-OH-DHA and 16 alpha-OH-A, on the other hand, reached a peak concentration at 36 weeks of gestation, and decreased thereafter. During active labor, unconjugated steroids tended to increase except E1. However, concentrations of T decreased during delivery as compared to those near term. Levels of DHA-S tended to fall as gestational weeks advanced, while those of 16 alpha-OH-DHA-S remained significantly high. It was indicated that a simultaneous determination of various steroids in the same blood sample obtained during pregnancy and at delivery was very useful in elucidating the role of steroids in the initiation of labor.

Androgens↗
PubMedDate not supplied

Effect of tamoxifen treatment on estrogen metabolism in postmenopausal women with advanced breast cancer.

The effect of tamoxifen therapy on plasma estrone and estradiol concentration, urinary excretion of estrone, estradiol, and estriol glucuronides, and metabolism of a tracer of 3H-estradiol was studied in 12 postmenopausal women with metastatic breast cancer. The most striking change observed was consistent increase in the 72-hour urinary recovery of total radioactivity after the tracer, from a mean of 47% to a mean of 61% of the dose. This increase was accounted for by a corresponding increase in the recovery of total glucuronide radioactivity, from a mean of 32% to a mean of 44% of the dose; there was no change in the proportions of estrone, estradiol, estriol, or 2-hydroxyestrone in the glucuronide fraction. The most likely explanation for this finding is that the estrogen-receptor-blocking effect of tamoxifen decreases estrogen uptake by various tissues and permits the estrogen to be excreted in the urine instead. There was also a small but consistent and significant decrease in plasma estrone (from 47 to 36 pg/ml) and estradiol (from 15 to 13 pg/ml), with no change in urinary excretion of estrogen glucuronides. The drop in plasma estrogen levels without a decrease in estrogen production suggests that tamoxifen may increase the metabolic and/or renal clearance of estrogen metabolites. There was no correlation between the observed effects of tamoxifen and the pretreatment estrogen-receptor status of the patient or her response to tamoxifen therapy.

Aged↗
PubMed1980

Binding of 2-hydroxyestradiol to rat anterior pituitary cell membranes.

We have studied the specific binding of 1,3,5(10)-estratrien-2,3,17 beta-triol (2-hydroxyestradiol) to an enriched membrane fraction isolated from the rat anterior pituitary gland. Specific [6,7-(3)H]2-hydroxyestradiol-17 beta ([3H]2-hydroxyestradiol) binding is saturable and displays a high and low affinity binding component. The apparent dissociation constants, KD, are 4 +/- 2 x 10(-10) and 2 x 10(-6) M with 13 fmol and 2.6 pmol bound/mg of protein, respectively. The specific high affinity binding increases linearly with increasing amounts of tissue protein. The binding is both temperature- and pH-dependent, with maximal binding at 37 degrees C and pH 7.4. The 2-hydroxyestradiol binding is shown to be stereospecific. Dopamine and spiroperidol (a dopamine antagonist) competitively inhibit the specific binding of [3H]2-hydroxyestradiol to the high affinity binding site with inhibition constants, KI, of 1 x 10(-6) M and 2 x 10(-5) M, respectively. Related catecholestrogens (2-hydroxyestrone and 2-hydroxyestriol) are also competitive inhibitors of [3H]2-hydroxyestradiol binding with KI values of 1.5 x 10(-5) M and 1.9 x 10(-5) M, respectively. None of the estrogens (estrone, estradiol, estriol) or 2-methoxyestrogen derivatives (2-methoxyestrone, 2-methoxyestradiol, 2-methoxyestriol) inhibits [3H]2-hydroxyestradiol binding at concentrations up to 10(-4) M. Norepinephrine, epinephrine, and serotonin are also ineffective as inhibitors at concentrations of 10(-5) M and inhibited less than 20% at 10(-4) M. Centrifugation through a stepwise discontinuous sucrose density gradient is used to separate subcellular components of the anterior pituitary cells. Approximately 90 per cent of the specific [3H]2-hydroxyestradiol binding is associated with the material at the 47.4 to 52.9% sucrose interface, the layer most highly enriched for 5'-nucleotidase (an enzyme marker for plasma membranes). Studies of tissue specificity indicate that specific 2-hydroxyestradiol binding sites are heterogeneously distributed in nervous tissue with the highest concentration of binding sites in the anterior pituitary, cerebral cortex, and hypothalamus and lower levels found in the thalamus and striatum. Low levels 2-hydroxyestradiol binding sites are also identified in liver and uterus. The present demonstration of specific 2-hydroxyestradiol binding to the anterior pituitary membrane provides information on the mechanism of catecholestrogen action.

Animals↗
PubMed1975

[Excretion of 7 estrogens during last days of human pregnancy].

The excretion of seven urinary estrogens was studied during the last two or three weeks of five normal pregnant women. A study of the urinary excretion curves demonstrated that 16 alpha-hydroxyestrone and 16-oxo-estradiol followed the same pattern with the particularity of presenting two excretion peaks which were persistently observed on the 8th or 7th day prior to delivery for the first one, and around the 4th or 3rd day prior to delivery for the second one. It is possible that there is a relation between this phenomenon and the onset of delivery.

Estrogens↗
PubMed1993

Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs.

A cDNA clone, designated UGT2B7 variant, encoding a 529-amino acid human liver microsomal uridine diphosphate-glucuronosyltransferase (UGT) was isolated from a lambda gt11 human liver cDNA library. UGT2B7 variant synthesized in COS-7 cells was screened for activity toward a range of clinically used drugs and other xenobiotics. The expressed enzyme glucuronidated several carboxylic acid-containing nonsteroidal antiinflammatory agents including, in order of relative substrate activity, naproxen, ketoprofen, ibuprofen, fenoprofen, tiaprofenic acid, benoxprofen, zomepirac, diflunisal and indomethacin. Additionally, the stereoselectivity of ketoprofen, naproxen (S/R ratio approximately unity) and ibuprofen (S/R ratio 1.62) glucuronidation by the UGT2B7 variant was shown to differ. Two other carboxylic acid-containing drugs (clofibric acid and valproic acid) and a limited range of drugs containing an alcohol or phenolic functional group were also glucoronidated by expressed UGT2B7 variant. The deduced amino sequence of UGT2B7 variant was shown to differ only in one amino acid (tyrosine for histidine at position 268) from a previously published uridine diphosphate-glucuronosyltransferase cDNA, UGT2B7. Like the previously reported enzyme, this variant efficiently glucuronidated hyodeoxycholic acid, estriol, 4-hydroxyestrone and 2-hydroxyestriol. It is, therefore, apparent that UGT2B7 variant has the capacity to glucuronidate with a degree of specificity both endogenous compounds and xenobiotics. Preferred substrates for UGT2B7 variant include xenobiotic carboxylic acids, polyhydroxylated estrogens and hyodeoxycholic acid.

Animals↗
PubMed1996

17 beta-Estradiol metabolism by hamster hepatic microsomes. Implications for the catechol-O-methyl transferase-mediated detoxication of catechol estrogens.

We have shown that the metabolism of 17 beta-estradiol in hamster liver microsomes is concentration-dependent. At low (< 25 microM) concentrations of 17 beta-estriol, 16 alpha-hydroxylase activity predominated, and estriol was the major metabolite. At higher concentrations (25-75 microM), 16 alpha-hydroxylation and aromatic hydroxylation at C2 contributed equally to 17 beta-estradiol metabolism. Aromatic C4-hydroxylation was maximal at 75 microM of 17 beta-estradiol and was always less than C2-hydroxylation. Dehydrogenation of the 17 beta-hydroxyl group to the ketone (estrone) was also observed, but both estrone and 2-hydroxyestrone were minor (approximately 3%) metabolites of 17 beta-estradiol, only detectable at concentrations of 50 microM and above. Catechol-O-methyl transferase (COMT) effectively converted both 2- and 4-hydroxyl-17 beta-estradiol to their corresponding monomethoxy metabolites. Effective reducing conditions are required for COMT activity, because catechol estrogens are readily oxidized to their corresponding ortho-quinones, and ascorbic acid is routinely added to assays of COMT activity. Interestingly, although ascorbic acid (1 mM) increased the recovery of 2- and 4-hydroxy-17 beta-estradiol from microsomal incubations, it decreased the recovery of the methoxy metabolites (approximately 40%). Since the enediol function of ascorbate resembles that of a catechol group, ascorbate is a substrate for COMT and probably competes with the catechol estrogens for methylation. Because previous studies describing the ability of COMT to inhibit the covalent binding of electrophilic reactive metabolites of [4-(14)C]17 beta-estradiol to microsomal protein were performed in the presence of high (100 mM) Mg2+ concentrations, we also investigated the effects of Mg2+ on 17 beta-estradiol metabolism. Concentrations of Mg2+ > 10 mM inhibited the metabolism of 17 beta-estradiol, as evidenced by i) the increased recovery of substrate; ii) a decrease in the formation of estriol, estrone, and 2-, and 4-hydroxy-17 beta-estradiol; iii) a decrease in the recovery of water-soluble metabolites when incubations were performed in the presence of glutathione (GSH) to trap the reactive electrophilic metabolites; and iv) a decrease in the amount of reactive electrophilic metabolites bound to microsomal protein. GSH also decreased the covalent binding of electrophilic metabolites of [4-(14)C]17 beta-estradiol to microsomal protein, with the concomitant formation of water-soluble metabolites. Thus, both COMT and GSH combine to limit the formation of electrophilic metabolites from 17 beta-estradiol. The relative importance of each of these pathways to the disposition of the catechol estrogens remains to be determined.

Animals↗
PubMed1997

Effect of dietary 2(3)-tert-butyl-4-hydroxyanisole on the metabolism and action of estradiol and estrone in female CD-1 mice.

Administration of 0.75% 2(3)-tert-butyl-4-hydroxyanisole (BHA) in AIN-76A diet to female CD-1 mice for 3 weeks increased liver microsomal glucuronidation of estradiol, estrone, 4-aminophenol, and 4-nitrophenol by 103, 187, 162, and 92%, respectively (at pH 7.4). The overall rate of NADPH-dependent metabolism of estradiol and estrone by liver microsomes of BHA-treated animals as determined by substrate disappearance was increased by 20-40% over that by liver microsomes from control animals. The rate of 2-hydroxylation of estradiol and estrone (the major metabolic pathway) was increased by 24-38%, the rate of formation of 6alpha-hydroxyestradiol plus 6beta-hydroxyestradiol was increased by 90-115%, and the rate of 6beta-hydroxyestrone formation (a minor metabolite formed in liver microsomes from control mice) was increased by approximately 370% over controls. In contrast, BHA administration had little or no effect on the liver microsomal formation of 4- and 16alpha-hydroxylated estradiol and estrone metabolites. Measurable levels of estradiol and estrone were observed in the serum and uterus of ovariectomized CD-1 mice at 30 min after a single i.p. injection of 100 or 300 ng of estradiol or estrone, and these levels were decreased by 30-60% in animals fed a 0.75% BHA diet for 18 days prior to the injection of estrogen. Feeding a 0.75% BHA-supplemented diet to ovariectomized CD-1 mice for 18 days inhibited the uterotropic effect of estradiol or estrone (45 or 75 ng/mouse, i.p. once daily for 3 days) as compared to the response of animals fed the control diet. BHA administration also inhibited estradiol- or estrone-stimulated [3H]thymidine incorporation into uterine DNA. In conclusion, feeding a 0.75% BHA-supplemented diet to female CD-1 mice for 2-3 weeks increased the activities of liver microsomal enzymes that catalyze uridine 5'-diphosphoglucuronic acid-dependent glucuronidation and NADPH-dependent oxidation of estradiol and estrone, enhanced the in vivo metabolism of these estrogens, and inhibited their uterotropic action.

Animals↗
PubMed1997

Characterization of rabbit UDP-glucuronosyltransferase UGT1A7: tertiary amine glucuronidation is catalyzed by UGT1A7 and UGT1A4.

A rabbit liver UDP-glucuronosyltransferase cDNA that is related to human and rat UGT1A7 has been identified. The predicted amino acid sequence of the UGT1A71 displays 80% similarity to that encoded by human HP4 (UGT1A9), but 81% to that predicted for human UGT1A7 and 77% to the rat UGT1A7 (UGTA2). The exons encoding human UGT1A7 and rat UGTA2 are the seventh of the series of cassette exons that flank the 3' common exon series of the UGT1A locus. Southern blot analysis demonstrates that the exon sequence encoding UGT1A71 is part of a larger cluster of highly related genes. The UGT1A71 RNA is expressed in both neonatal and adult liver, and unlike rat UGT1A2 which is inducible with Ah receptor ligands such as polycyclic aromatic hydrocarbons, rabbit UGT1A7 is not regulated when animals are exposed to these inducers. Following expression of UGT171 in COS-1 cells, glucuronidation activity was identified for small phenolic molecules like 4-nitrophenyl, bulky phenols as represented by 4-hydroxybiphenol and octylgallate, as well as 4-hydroxyestrone. In addition, UGT1A71 possesses catalytic activity toward tertiary amines like the tricyclic antidepressant imipramine. The pattern of UGT1A71 glucuronidation is similar to that observed for human UGT1A9, except tertiary amines are not subject to glucuronidation by human UGT1A9. Glucuronidation of tertiary amines is catalyzed principally by human UGT1A4 as well as rabbit UGT1A4. Although rabbit UGT1A7 catalyzes the formation of quarternary ammonium glucuronides, the Vmax is considerably less than that observed for rabbit UGT1A4. Overall, the characterization of rabbit UGT1A7 suggests that this protein represents the ortholog of the human UGT1A7, which to date has not been identified.

Amines↗
PubMed1998

Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis?

Catechol estrogens (2- or 4-hydroxyestradiol and 2- or 4-hydroxyestrone) are chemically reactive estrogen metabolites that are O-methylated to less polar monomethyl ethers by catechol-O-methyltransferase, an enzyme present in many tissues such as the liver, kidney, brain, placenta, uterus, and mammary gland. In the present report, we review recent studies on the antitumorigenic and antiangiogenic effects of exogenously administered 2-methoxyestradiol in vitro and in vivo. We also discuss data that suggest that endogenous formation of 2-methoxyestradiol (and its 2-hydroxyestradiol precursor) may have a protective effect on estrogen-induced cancers in target organs. Although the molecular mechanism of action of 2-methoxyestradiol is not clear, we suggest that some unique effects of 2-methoxyestradiol may be mediated by a specific intracellular effector or receptor that is refractory to the parent hormone, estradiol. Additional research is needed to identify factors that regulate the metabolic formation and disposition of 2-methoxyestradiol in liver and in target cells and to evaluate the effects of modulating 2-methoxyestradiol formation on estrogen-induced carcinogenesis.

2-Methoxyestradiol↗